Nature Medicine | Spoonful of Medicine

Red blood cell production relies on white blood cell help

Red and white blood cells
Red blood cell production in the bone marrow is a precarious process. Too few RBCs and you can become anemic; too many and you could be suffering from polycythemia vera, a rare, so-called ‘myeloproliferative’ genetic disorder marked by an abnormally high RBC count. Now, researchers have identified a surprising player in the regulation of RBC production under these disease conditions. Reporting online today in Nature Medicine, two independent teams describe the pivotal role of macrophages—amoeba-like white blood cells responsible for digesting harmful foreign microbes and removing old or dying cells—for generating RBCs in both anemic and over-proliferative conditions.

In one study, geneticist Stefano Rivella and his colleagues at the Weill Cornell Medical College in New York administered a drug that selectively kills macrophages in a mouse model of polycythemia vera. In these mice, RBCs are generated at almost twice the normal amount, leading to viscous blood, enlarged organs and increased risk for strokes and heart disease. The drug, called clodronate, appeared to cure these symptoms, however, drastically lowering macrophage population and bringing RBC counts back to normal levels compared with a control group of animals treated with saline.

These findings were independently confirmed by Paul Frenette, a stem cell biologist at the Albert Einstein College of Medicine, also in New York. His team used a genetically modified mouse in which macrophages expressed a gene that made them vulnerable to a toxin and arrived at similar conclusions. “When we depleted macrophages in this disease, we actually corrected the disease,” Frenette says. “Maybe this could be a new therapy for this type of disease, which is unexpected.”

Beta testing

Rivella and his group also studied beta-thalassemia, another inherited blood disorder characterized by lowered RBC counts and severe anemia. Paradoxically, RBC precursor cells are actually overproduced in this disease, but they never fully mature and subsequently build up in the spleen and liver, leading to organ enlargement. When treated with clodronate, however, genetically modified mice with a beta-thalassemia-like condition showed statistically significant increased RBC counts. Rivella chalks this effect up to reduced precursor cell numbers and organ size, allowing better circulation of healthy cells. “Take out the macrophages and the ability of [RBC precursors] to expand and proliferate is decreased,” he says.

Interestingly, when normal mice were macrophage-depleted, there were no observable effects on RBC levels. Both Frenette and Rivella believe that this indicates macrophages modulate RBC production only during stress or abnormal conditions. The precise mechanisms for this new stress-related role remain opaque, although Frenette’s group showed evidence that an adhesion molecule known as VCAM1 and a bone marrow protein known as BMP 4 could play a part.

For now, patients suffering from disorders such as polycythemia vera and beta-thalassemia will have to wait until these mechanisms are fully understood. Macrophage depletion in both studies was temporary, as cessation of treatment led to macrophage and symptom recovery. In addition, macrophage depletion can have severe consequences in immunity, bone formation and many other systems. Clodronate “is a really great drug to do these experiments, but it’s not something I’d suggest to patients,” says Rivella.

On the flipside, boosting macrophage levels could prove beneficial in some settings. For instance, Frenette’s group gave mice bone marrow transplants and showed that wiping out macrophage levels significantly delayed RBC recovery. The finding, Frenette says, “would suggest that methods to improve macrophage functional recovery might be useful in a situation such as bone marrow transplantation where you need to make more red blood cells faster.”

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